This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background

In a phase I study of angiotensin-(1–7) [Ang-(1–7)], clinical benefit was associated with reduction in plasma placental growth factor (PlGF) concentrations. The current study examines Ang-(1–7) induced changes in biomarkers according to cancer type and investigates mechanisms of action engaged in vitro.

Methods

Plasma biomarkers were measured prior to Ang-(1–7) administration as well as 1, 2, 3, 4, and 6hours after treatment. Tests for interaction were performed to determine the impact of cancer type on angiogenic hormone levels. If a positive interaction was detected, treatment-induced biomarker changes for individual cancer types were assessed. To investigate mechanisms of action, in vitro growth assays were performed using a murine endothelioma cell line (EOMA). PCR arrays were performed to identify and statistically validate genes that were altered by Ang-(1–7) treatment in these cells.

Results

Tests for interaction controlled for dose cohort and clinical response indicated a significant impact of cancer type on post-treatment VEGF and PlGF levels. Following treatment, PlGF levels decreased over time in patients with sarcoma (P=.007). Treatment of EOMA cells with increasing doses of Ang-(1–7) led to significant growth suppression at doses as low as 100 nM. PCR arrays identified 18 genes that appeared to have altered expression after Ang-(1–7) treatment. Replicate analyses confirmed significant changes in 8 genes including reduction in PlGF (P=.04) and hypoxia inducible factor 1α (HIF-1α) expression (P<.001).

Conclusions

Ang-(1–7) has clinical and pre-clinical activity for vascular sarcomas that is linked to reduced HIF-1α and PlGF expression.